Approximately 2 million American sustain traumatic head injuries annually, most of which are considered mild. Despite the seemingly mild proportions of the trauma sustained, many injured individuals develop shortly after a debilitating headache, which can persist for months and even years. In many patients with post traumatic headache (PTH), treatment remains unsatisfactory leading to suffering and poor quality of life. Despite the relatively high prevalence of PTH, its underlying pathophysiology remains poorly defined. This lack of understanding greatly hinders the development evidence-based pain management to alleviate PTH pain. In preliminary experiments, we have used a rat model of mild traumatic closed-head injury. We have found that such relatively mild trauma can promote the activation of putative nociceptive afferent neurons that innervate the periosteal lining of the skull. Our data also indicate that similar to patients suffering from PTH, head trauma in rats can also lead to pericranial tactile pain hypersensitivity. Finally, our data suggests that mild head trauma promotes persistent inflammation within the skull's periosteum, a process which could serve as a mechanism that initiates and sustains the activation of calvarial periosteal afferents and the ensuing PTH and its related pericranial pain hypersensitivity. Based on this pilot data, we propose a series of exploratory single-unit electrophysiological recording, behavioral, histological and pharmacological studies that will begin to address our working hypothesis that upon head trauma, the skull's periosteum serves as a key peripheral site that contributes to the development of PTH. We propose to employ a rat model of mild closed-head injury to address the following 3 specific aims: Aim 1 will test the hypothesis that following mild head trauma, calvarial periosteal afferents develop persistent ongoing activity and become hypersensitive to mechanical stimuli. Aim 2 will test the hypothesis that mild head injury-evoked activation and hypersensitivity of calvarial periosteal afferents is manifested behaviorally as pericranial tactile hypersensitivity as seen in PTH patients. Aim 3 will to test the hypothesis that mild head trauma leads to persistent inflammation within the calvarial periosteum, and that this process, in particular local action of inflammatory mast cells, contributes to the development of periosteal afferent activation/sensitization and pericranial tactile hypersensitivity. Results from this study will begin to shed more light on the pathophysiology of PTH and potentially lead to the expansion of the targets of interventions that can be used to alleviate the pain of PTH. Data collected will lead to further testable hypotheses on the cellular and molecular changes that contribute to the development of PTH. PUBLIC HEALTH RELEVANCE: Persistent post traumatic headache (PTH) after mild head injury remains hard to manage in part due to the poor understanding of the pathophysiology underlying this headache syndrome. The proposed study will employ a rodent model of traumatic closed-head injury to examine the relative contribution of the skull's periosteum in mediating PTH pain. As a result of this research, new targets and pharmacological interventions may be explored to alleviate the pain of PTH.